bims-musmir 2024-07-14 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2024–07–14
twenty-one papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

PINK1 regulated mitophagy is evident in skeletal muscles.
Role of TRPC6 in apoptosis of skeletal muscle ischemia/reperfusion injury.
Maintaining mitochondrial NAD+ homeostasis is key for heat-induced skeletal muscle injury prevention despite presence of intracellular cation alterations.
Tumour-induced alterations in single-nucleus transcriptome of atrophying muscles indicate enhanced protein degradation and reduced oxidative metabolism.
Characterization of Proteome Changes in Aged and Collagen VI-Deficient Human Pericyte Cultures.
Reduced oxidative capacity of skeletal muscle mitochondria is a fundamental consequence of adult ageing.
KLF13 restrains Dll4-muscular Notch2 axis to improve the muscle atrophy.
The IRE1α/XBP1 signaling axis drives myoblast fusion in adult skeletal muscle.
Reduced oxidative capacity of skeletal muscle IS NOT an inevitable consequence of adult ageing.
Cancerous Conditions Accelerate the Aging of Skeletal Muscle via Mitochondrial DNA Damage.
Protein biomarker signature in patients with spinal and bulbar muscular atrophy.
Rebuttal: reduced oxidative capacity of skeletal muscle IS NOT an inevitable consequence of adult ageing.
Deletion of miR-146a enhances therapeutic protein restoration in model of dystrophin exon skipping.
Dynamics of single-nuclei transcriptomic profiling of adipose tissue from diverse anatomical locations during mouse aging process.
The role of interleukin-6 family cytokines in cancer cachexia.
Treadmill running and mechanical overloading improved the strength of the plantaris muscle in the dystrophin-desmin double knockout (DKO) mouse.
Muscle mitochondrial function is impaired in adults with type 1 diabetes.
RNA editing regulates glutamatergic synapses in the frontal cortex of a molecular subtype of Amyotrophic Lateral Sclerosis.
Lactate promotes fatty acid oxidation by the TCA cycle and mitochondrial respiration in muscles of obese mice.
Mitochondrion-to-nucleus communication mediated by RNA export: a survey of potential mechanisms and players across eukaryotes.
Reversal of cognitive deficits in FUSR521G amyotrophic lateral sclerosis mice by arimoclomol and a class I histone deacetylase inhibitor independent of heat shock protein induction.

Autophagy Rep. 2024 Mar 11. 3(1): 2326402

PINK1 regulated mitophagy is evident in skeletal muscles.

Francois Singh, Lea Wilhelm, Alan R Prescott, Kevin Ostacolo, Jin-Feng Zhao, Margret H Ogmundsdottir, Ian G Ganley.

  PINK1, mutated in familial forms of Parkinson's disease, initiates mitophagy following mitochondrial depolarization. However, it is difficult to monitor this pathway physiologically in mice as loss of PINK1 does not alter basal mitophagy levels in most tissues. To further characterize this pathway in vivo, we used mito-QC mice in which loss of PINK1 was combined with the mitochondrial-associated POLGD257A mutation. We focused on skeletal muscle as gene expression data indicates that this tissue has the highest PINK1 levels. We found that loss of PINK1 in oxidative hindlimb muscle significantly reduced mitophagy. Of interest, the presence of the POLGD257A mutation, while having a minor effect in most tissues, restored levels of muscle mitophagy caused by the loss of PINK1. Although our observations highlight that multiple mitophagy pathways operate within a single tissue, we identify skeletal muscle as a tissue of choice for the study of PINK1-dependant mitophagy under basal conditions.

Keywords:  PINK1; POLG; Parkinson’s; mitophagy; muscle; mutator

DOI:  https://doi.org/10.1080/27694127.2024.2326402
Cell Signal. 2024 Jul 04. pii: S0898-6568(24)00257-2. [Epub ahead of print]121 111289

Role of TRPC6 in apoptosis of skeletal muscle ischemia/reperfusion injury.

Dong-Ge Xie, Jun-Hao Li, Yun-Long Zhong, Han Han, Jia-Ji Zhang, Zhong-Qing Zhang, Shou-Tian Li.

   BACKGROUND: Skeletal muscle ischaemia-reperfusion injury (IRI) is a prevalent condition encountered in clinical practice, characterised by muscular dystrophy. Owing to limited treatment options and poor prognosis, it can lead to movement impairments, tissue damage, and disability. This study aimed to determine and verify the influence of transient receptor potential canonical 6 (TRPC6) on skeletal muscle IRI, and to explore the role of TRPC6 in the occurrence of skeletal muscle IRI and the signal transduction pathways activated by TRPC6 to provide novel insights for the treatment and intervention of skeletal muscle IRI.
METHODS: In vivo ischaemia/reperfusion (I/R) and in vitro hypoxia/reoxygenation (H/R) models were established, and data were comprehensively analysed at histopathological, cellular, and molecular levels, along with the evaluation of the exercise capacity in mice.
RESULTS: By comparing TRPC6 knockout mice with wild-type mice, we found that TRPC6 knockout of TRPC6 could reduced skeletal muscle injury after I/R or H/R, of skeletal muscle, so as therebyto restoringe some exercise capacity inof mice. TRPC6 knockdown can reduced Ca2+ overload in cells, therebyo reducinge apoptosis. In additionAdditionally, we also found that TRPC6 functionsis not only a key ion channel involved in skeletal muscle I/R injury, but also can affects Ca2+ levels and then phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signalling pathway. by knocking downTherefore, knockdown of TRPC6, so as to alleviated the injury inducedcaused by skeletal muscle I/R or and H/R.
CONCLUSIONS: These findingsdata indicate that the presence of TRPC6 exacerbatescan aggravate the injury of skeletal muscle injury after I/Rischemia/reperfusion, leading towhich not only causes Ca2+ overload and apoptosis., Additionally, it impairsbut also reduces the self- repair ability of cells by inhibiting the expression of the PI3K/Akt/mTOR signalling pathway. ETo exploringe the function and role of TRPC6 in skeletal muscle maycan presentprovide a novelew approachidea for the treatment of skeletal muscle ischemia/reperfusion injury.

Keywords:  Akt; Apoptosis; Ca(2+); Ischemia/reperfusion injury; PI3K; Skeletal muscle; TRPC6; mTOR

DOI:  https://doi.org/10.1016/j.cellsig.2024.111289
Appl Physiol Nutr Metab. 2024 Jul 09.

Maintaining mitochondrial NAD+ homeostasis is key for heat-induced skeletal muscle injury prevention despite presence of intracellular cation alterations.

Yifan Chen, Tianzheng Yu, Patricia Deuster.

Mitochondrial dysfunction is implicated in heat-induced skeletal muscle injury and its underlying mechanisms remain unclear. Evidence suggests that cellular ions and molecules, including divalent cations and adenine nucleotides, are involved in the regulation of mitochondrial function. In this study, we examined Ca2+, Mg2+, and NAD+ levels in mouse C2C12 myoblasts and skeletal muscle in response to heat exposure. During heat exposure, mitochondrial Ca2+ levels increased significantly, whereas cytosolic C2+ levels remained unaltered. The mitochondrial Ca2+ levels in the skeletal muscle of heat-exposed mice were 28% higher, compared to control mice. No changes in cytosolic Ca2+ were detected between the two groups. Following heat exposure, cytosolic and mitochondrial Mg2+ levels were reduced by 47% and 23% in C2C12 myoblasts, and by 51% and 44% in mouse skeletal muscles, respectively. In addition, heat exposure decreased mitochondrial NAD+ levels by 32% and 26% in C2C12 myoblasts and mouse skeletal muscles, respectively. Treatment with the NAD+ precursor nicotinamide riboside (NR) partially prevented heat-induced depletion of NAD+. Additionally, NR significantly reduced heat-increased mitochondrial fission, mitochondrial depolarization, and apoptosis in C2C12 myoblasts and mouse skeletal muscles. No effects of NR on heat-induced changes in intracellular Ca2+ and Mg2+ levels were observed. This study provides the in vitro and in vivo evidence that acute heat stress causes alterations in mitochondrial Ca2+, Mg2+, and NAD+ homeostasis. Our results suggest mitochondrial NAD+> homeostasis as a therapeutic target for the prevention of heat-induced skeletal muscle injury.

DOI: https://doi.org/10.1139/apnm-2024-0157
J Cachexia Sarcopenia Muscle. 2024 Jul 13.

Tumour-induced alterations in single-nucleus transcriptome of atrophying muscles indicate enhanced protein degradation and reduced oxidative metabolism.

Samet Agca, Aylin Domaniku-Waraich, Sevval Nur Bilgic, Melis Sucuoglu, Meric Dag, Sukru Anil Dogan, Serkan Kir.

   BACKGROUND: Tumour-induced skeletal muscle wasting in the context of cancer cachexia is a condition with profound implications for patient survival. The loss of muscle mass is a significant clinical obstacle and is linked to reduced tolerance to chemotherapy and increased frailty. Understanding the molecular mechanisms driving muscle atrophy is crucial for the design of new therapeutics.
METHODS: Lewis lung carcinoma tumours were utilized to induce cachexia and muscle atrophy in mice. Single-nucleus libraries of the tibialis anterior (TA) muscle from tumour-bearing mice and their non-tumour-bearing controls were constructed using 10X Genomics applications following the manufacturer's guidelines. RNA sequencing results were analysed with Cell Ranger software and the Seurat R package. Oxygen consumption of mitochondria isolated from TA muscle was measured using an Oroboros O2k-FluoRespirometer. Mouse primary myotubes were treated with a recombinant ectodysplasin A2 (EDA-A2) protein to activate EDA-A2 receptor (EDA2R) signalling and study changes in gene expression and oxygen consumption.
RESULTS: Tumour-bearing mice were sacrificed while exhibiting moderate cachexia. Average TA muscle weight was reduced by 11% (P = 0.0207) in these mice. A total of 12 335 nuclei, comprising 6422 nuclei from the control group and 5892 nuclei from atrophying muscles, were studied. The analysis of single-nucleus transcriptomes identified distinct myonuclear gene signatures and a shift towards type IIb myonuclei. Muscle atrophy-related genes, including Atrogin1, MuRF1 and Eda2r, were upregulated in these myonuclei, emphasizing their crucial roles in muscle wasting. Gene set enrichment analysis demonstrated that EDA2R activation and tumour inoculation led to similar expression patterns in muscle cells, including the stimulation of nuclear factor-kappa B, Janus kinase-signal transducer and activator of transcription and transforming growth factor-beta pathways and the suppression of myogenesis and oxidative phosphorylation. Muscle oxidative metabolism was suppressed by both tumours and EDA2R activation.
CONCLUSIONS: This study identified tumour-induced transcriptional changes in muscle tissue at single-nucleus resolution and highlighted the negative impact of tumours on oxidative metabolism. These findings contribute to a deeper understanding of the molecular mechanisms underlying muscle wasting.

Keywords:  EDA2R signalling; cancer cachexia; single‐nucleus RNA sequencing; skeletal muscle atrophy

DOI:  https://doi.org/10.1002/jcsm.13540
Int J Mol Sci. 2024 Jun 28. pii: 7118. [Epub ahead of print]25(13):

Characterization of Proteome Changes in Aged and Collagen VI-Deficient Human Pericyte Cultures.

Manuela Moriggi, Enrica Torretta, Matilde Cescon, Loris Russo, Ilaria Gregorio, Paola Braghetta, Patrizia Sabatelli, Cesare Faldini, Luciano Merlini, Cesare Gargioli, Paolo Bonaldo, Cecilia Gelfi, Daniele Capitanio.

  Pericytes are a distinct type of cells interacting with endothelial cells in blood vessels and contributing to endothelial barrier integrity. Furthermore, pericytes show mesenchymal stem cell properties. Muscle-derived pericytes can demonstrate both angiogenic and myogenic capabilities. It is well known that regenerative abilities and muscle stem cell potential decline during aging, leading to sarcopenia. Therefore, this study aimed to investigate the potential of pericytes in supporting muscle differentiation and angiogenesis in elderly individuals and in patients affected by Ullrich congenital muscular dystrophy or by Bethlem myopathy, two inherited conditions caused by mutations in collagen VI genes and sharing similarities with the progressive skeletal muscle changes observed during aging. The study characterized pericytes from different age groups and from individuals with collagen VI deficiency by mass spectrometry-based proteomic and bioinformatic analyses. The findings revealed that aged pericytes display metabolic changes comparable to those seen in aging skeletal muscle, as well as a decline in their stem potential, reduced protein synthesis, and alterations in focal adhesion and contractility, pointing to a decrease in their ability to form blood vessels. Strikingly, pericytes from young patients with collagen VI deficiency showed similar characteristics to aged pericytes, but were found to still handle oxidative stress effectively together with an enhanced angiogenic capacity.

Keywords:  Bethlem myopathy; Ullrich congenital muscular dystrophy; muscle aging; myogenic differentiation; pericyte; skeletal muscle

DOI:  https://doi.org/10.3390/ijms25137118
J Physiol. 2024 Jul 06.

Reduced oxidative capacity of skeletal muscle mitochondria is a fundamental consequence of adult ageing.

David J Marcinek, Luigi Ferrucci.



Keywords:  ageing; magnetic resonance; mitochondria; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1113/JP285040
J Cachexia Sarcopenia Muscle. 2024 Jul 08.

KLF13 restrains Dll4-muscular Notch2 axis to improve the muscle atrophy.

Shu Yang, Lijiao Xiong, Guangyan Yang, Jiaqing Xiang, Lixing Li, Lin Kang, Zhen Liang.

   BACKGROUND: Muscle atrophy can cause muscle dysfunction and weakness. Krüppel-like factor 13 (KLF13), a central regulator of cellular energy metabolism, is highly expressed in skeletal muscles and implicated in the pathogenesis of several diseases. This study investigated the role of KLF13 in muscle atrophy, which could be a novel therapeutic target.
METHODS: The effects of gene knockdown and pharmacological targeting of KLF13 on skeletal muscle atrophy were investigated using cell-based and animal models. Clofoctol, an antibiotic and KLF13 agonist, was also investigated as a candidate for repurposing. The mechanisms related to skeletal muscle atrophy were assessed by measuring the expression levels and activation statuses of key regulatory pathways and validated using gene knockdown and RNA sequencing.
RESULTS: In a dexamethasone-induced muscle atrophy mouse model, the KLF13 knockout group had decreased muscle strength (N) (1.77 ± 0.10 vs. 1.48 ± 0.16, P < 0.01), muscle weight (%) [gastrocnemius (Gas): 76.0 ± 5.69 vs. 60.7 ± 7.23, P < 0.001; tibialis anterior (TA): 75.8 ± 6.21 vs. 67.5 ± 5.01, P < 0.05], and exhaustive running distance (m) (495.5 ± 64.8 vs. 315.5 ± 60.9, P < 0.05) compared with the control group. KLF13 overexpression preserved muscle mass (Gas: 100 ± 6.38 vs. 120 ± 14.4, P < 0.01) and the exhaustive running distance (423.8 ± 59.04 vs. 530.2 ± 77.45, P < 0.05) in an in vivo diabetes-induced skeletal muscle atrophy model. Clofoctol treatment protected against dexamethasone-induced muscle atrophy. Myotubes treated with dexamethasone, an atrophy-inducing glucocorticoid, were aggravated by KLF13 knockout, but anti-atrophic effects were achieved by inducing KLF13 overexpression. We performed a transcriptome analysis and luciferase reporter assays to further explore this mechanism, finding that delta-like 4 (Dll4) was a novel target gene of KLF13. The KLF13 transcript repressed Dll4, inhibiting the Dll4-Notch2 axis and preventing muscle atrophy. Dexamethasone inhibited KLF13 expression by inhibiting myogenic differentiation 1 (i.e., MYOD1)-mediated KLF13 transcriptional activation and promoting F-Box and WD repeat domain containing 7 (i.e., FBXW7)-mediated KLF13 ubiquitination.
CONCLUSIONS: This study sheds new light on the mechanisms underlying skeletal muscle atrophy and potential drug targets. KLF13 regulates muscle atrophy and is a potential therapeutic target. Clofoctol is an attractive compound for repurposing studies to treat skeletal muscle atrophy.

Keywords:  Clofoctol; DLL4; KLF13; Notch; Sarcopenia

DOI:  https://doi.org/10.1002/jcsm.13538
EMBO Rep. 2024 Jul 09.

The IRE1α/XBP1 signaling axis drives myoblast fusion in adult skeletal muscle.

Aniket S Joshi, Meiricris Tomaz da Silva, Anirban Roy, Tatiana E Koike, Mingfu Wu, Micah B Castillo, Preethi H Gunaratne, Yu Liu, Takao Iwawaki, Ashok Kumar.

  Skeletal muscle regeneration involves a signaling network that regulates the proliferation, differentiation, and fusion of muscle precursor cells to injured myofibers. IRE1α, one of the arms of the unfolded protein response, regulates cellular proteostasis in response to ER stress. Here, we demonstrate that inducible deletion of IRE1α in satellite cells of mice impairs skeletal muscle regeneration through inhibiting myoblast fusion. Knockdown of IRE1α or its downstream target, X-box protein 1 (XBP1), also inhibits myoblast fusion during myogenesis. Transcriptome analysis revealed that knockdown of IRE1α or XBP1 dysregulates the gene expression of molecules involved in myoblast fusion. The IRE1α-XBP1 axis mediates the gene expression of multiple profusion molecules, including myomaker (Mymk). Spliced XBP1 (sXBP1) transcription factor binds to the promoter of Mymk gene during myogenesis. Overexpression of myomaker in IRE1α-knockdown cultures rescues fusion defects. Inducible deletion of IRE1α in satellite cells also inhibits myoblast fusion and myofiber hypertrophy in response to functional overload. Collectively, our study demonstrates that IRE1α promotes myoblast fusion through sXBP1-mediated up-regulation of the gene expression of multiple profusion molecules, including myomaker.

Keywords:  IRE1; Muscle Regeneration; Myoblast Fusion; XBP1; and Myomaker

DOI:  https://doi.org/10.1038/s44319-024-00197-4
J Physiol. 2024 Jul 06.

Reduced oxidative capacity of skeletal muscle IS NOT an inevitable consequence of adult ageing.

Ian R Lanza, Christopher W Sundberg, Jane A Kent.



Keywords:  ageing; mitochondria; oxidative phosphorylation; skeletal muscle

DOI:  https://doi.org/10.1113/JP285042
Int J Mol Sci. 2024 Jun 27. pii: 7060. [Epub ahead of print]25(13):

Cancerous Conditions Accelerate the Aging of Skeletal Muscle via Mitochondrial DNA Damage.

Yi Luo, Rina Fujiwara-Tani, Isao Kawahara, Kei Goto, Shota Nukaga, Ryoichi Nishida, Chie Nakashima, Takamitsu Sasaki, Yoshihiro Miyagawa, Ruiko Ogata, Kiyomu Fujii, Hitoshi Ohmori, Hiroki Kuniyasu.

  Skeletal muscle aging and sarcopenia result in similar changes in the levels of aging markers. However, few studies have examined cancer sarcopenia from the perspective of aging. Therefore, this study investigated aging in cancer sarcopenia and explored its causes in vitro and in vivo. In mouse aging, in vitro cachexia, and mouse cachexia models, skeletal muscles showed similar changes in aging markers including oxidative stress, fibrosis, reduced muscle differentiation potential, and telomere shortening. Furthermore, examination of mitochondrial DNA from skeletal muscle revealed a 5 kb deletion in the major arc; truncation of complexes I, IV, and V in the electron transport chain; and reduced oxidative phosphorylation (OXPHOS). The mouse cachexia model demonstrated high levels of high-mobility group box-1 (HMGB1) and tumor necrosis factor-α (TNFα) in cancer ascites. Continuous administration of neutralizing antibodies against HMGB1 and TNFα in this model reduced oxidative stress and abrogated mitochondrial DNA deletion. These results suggest that in cancer sarcopenia, mitochondrial oxidative stress caused by inflammatory cytokines leads to mitochondrial DNA damage, which in turn leads to decreased OXPHOS and the promotion of aging.

Keywords:  aging; cancer sarcopenia; mitochondria; mitochondrial DNA

DOI:  https://doi.org/10.3390/ijms25137060
JCI Insight. 2024 May 30. pii: e176383. [Epub ahead of print]9(13):

Protein biomarker signature in patients with spinal and bulbar muscular atrophy.

Andrew Tn Tebbenkamp, Spencer B Huggett, Vittoria Lombardi, Luca Zampedri, Abdullah AlQahtani, Angela Kokkinis, Andrea Malaspina, Carlo Rinaldi, Christopher Grunseich, Pietro Fratta, Vissia Viglietta.

  Spinal and bulbar muscular atrophy (SBMA) is a slowly progressing disease with limited sensitive biomarkers that support clinical research. We analyzed plasma and serum samples from patients with SBMA and matched healthy controls in multiple cohorts, identifying 40 highly reproducible SBMA-associated proteins out of nearly 3,000 measured. These proteins were robustly enriched in gene sets of skeletal muscle expression and processes related to mitochondria and calcium signaling. Many proteins outperformed currently used clinical laboratory tests (e.g., creatine kinase [CK]) in distinguishing patients from controls and in their correlations with clinical and functional traits in patients. Two of the 40 proteins, Ectodysplasin A2 receptor (EDA2R) and Repulsive guidance molecule A (RGMA), were found to be associated with decreased survival and body weight in a mouse model of SBMA. In summary, we identified what we believe to be a robust and novel set of fluid protein biomarkers in SBMA that are linked with relevant disease features in patients and in a mouse model of disease. Changes in these SBMA-associated proteins could be used as an early predictor of treatment effects in clinical trials.

Keywords:  Genetic diseases; Muscle biology; Neuromuscular disease; Neuroscience; Proteomics

DOI:  https://doi.org/10.1172/jci.insight.176383
J Physiol. 2024 Jul 06.

Rebuttal: reduced oxidative capacity of skeletal muscle IS NOT an inevitable consequence of adult ageing.

Ian R Lanza, Christopher W Sundberg, Jane A Kent.



Keywords:  ageing; mitochondria; muscle; oxidative phosphorylation

DOI:  https://doi.org/10.1113/JP286695
Mol Ther Nucleic Acids. 2024 Sep 10. 35(3): 102228

Deletion of miR-146a enhances therapeutic protein restoration in model of dystrophin exon skipping.

Nikki M McCormack, Kelsey A Calabrese, Christina M Sun, Christopher B Tully, Christopher R Heier, Alyson A Fiorillo.

  Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by the absence of dystrophin protein. One current DMD therapeutic strategy, exon skipping, produces a truncated dystrophin isoform using phosphorodiamidate morpholino oligomers (PMOs). However, the potential of exon skipping therapeutics has not been fully realized as increases in dystrophin protein have been minimal in clinical trials. Here, we investigate how miR-146a-5p, which is highly elevated in dystrophic muscle, impacts dystrophin protein levels. We find inflammation strongly induces miR-146a in dystrophic, but not wild-type myotubes. Bioinformatics analysis reveals that the dystrophin 3' UTR harbors a miR-146a binding site, and subsequent luciferase assays demonstrate miR-146a binding inhibits dystrophin translation. In dystrophin-null mdx52 mice, co-injection of miR-146a reduces dystrophin restoration by an exon 51 skipping PMO. To directly investigate how miR-146a impacts therapeutic dystrophin rescue, we generated mdx52 with body-wide miR-146a deletion (146aX). Administration of an exon skipping PMO via intramuscular or intravenous injection markedly increases dystrophin protein levels in 146aX vs. mdx52 muscles while skipped dystrophin transcript levels are unchanged supporting a post-transcriptional mechanism of action. Together, these data show that miR-146a expression opposes therapeutic dystrophin restoration, suggesting miR-146a inhibition warrants further research as a potential DMD exon skipping co-therapy.

Keywords:  Becker muscular dystrophy; Duchenne muscular dystrophy; MT: Non-coding RNAs; RNA therapeutics; antisense oligonucleotides; dystrophin; exon skipping; miR-146a-5p; microRNA

DOI:  https://doi.org/10.1016/j.omtn.2024.102228
Sci Rep. 2024 Jul 12. 14(1): 16093

Dynamics of single-nuclei transcriptomic profiling of adipose tissue from diverse anatomical locations during mouse aging process.

Yujie Wu, Ying Sun, Long Chen, Xingyan Tong, Can Liu, Lu Lu, Rui Zhang, Siyuan Wang, Ziyu Chen, Jiaman Zhang, Ziyin Han, Bo Zeng, Mingzhou Li, Long Jin.

Adipose tissue plays critical roles in an individual's aging process. In this research, we use single-nucleus RNA sequencing to create highly detailed transcriptional maps of subcutaneous adipose tissue and visceral adipose tissue in young and aged mice. We comprehensively identify the various cell types within the white adipose tissue of mice, our study has elucidated seven distinct cell types within this tissue. Further analyses focus on adipocytes, fibro-adipogenic progenitors, and immune cells, revealing age-related declines in the synthetic metabolic activity of adipocytes, diminished immune regulation, and reduced maturation or proliferation of fibroblasts in undifferentiated adipocytes. We confirm the presence of distinct subpopulations of adipocytes, highlighting decreases in adipogenesis subgroups due to aging. Additionally, we uncover a reduction in immune cell subpopulations, driven by age-associated immune system dysregulation. Furthermore, pseudo-time analyses indicate that Adipocyte1 represents the 'nascent' phase of adipocyte development, while Adipocyte2 represents the 'mature' phase. We use cell-cell interaction to explore the age-dependent complexities of the interactions between FAPs and adipocytes, and observed increased expression of the inflammation-related Retn-Tlr4 interaction in older mice, while the anti-inflammatory Angpt1-Tek interaction was only detected in young mice. These transcriptional profiles serve as a valuable resource for understanding the functional genomics underlying metabolic disorders associated with aging in human adipose tissue.

DOI: https://doi.org/10.1038/s41598-024-66918-w
FEBS J. 2024 Jul 08.

The role of interleukin-6 family cytokines in cancer cachexia.

Samet Agca, Serkan Kir.

  Cachexia is a wasting syndrome that manifests in more than half of all cancer patients. Cancer-associated cachexia negatively influences the survival of patients and their quality of life. It is characterized by a rapid loss of adipose and skeletal muscle tissues, which is partly mediated by inflammatory cytokines. Here, we explored the crucial roles of interleukin-6 (IL-6) family cytokines, including IL-6, leukemia inhibitory factor, and oncostatin M, in the development of cancer cachexia. These cytokines have been shown to exacerbate cachexia by promoting the wasting of adipose and muscle tissues, activating mechanisms that enhance lipolysis and proteolysis. Overlapping effects of the IL-6 family cytokines depend on janus kinase/signal transducer and activator of transcription 3 signaling. We argue that the blockade of these cytokine pathways individually may fail due to redundancy and future therapeutic approaches should target common downstream elements to yield effective clinical outcomes.

Keywords:  adipose tissue wasting; cancer cachexia; interleukin‐6; leukemia inhibitory factor; muscle atrophy; oncostatin M

DOI:  https://doi.org/10.1111/febs.17224
J Physiol. 2024 Jul 09.

Treadmill running and mechanical overloading improved the strength of the plantaris muscle in the dystrophin-desmin double knockout (DKO) mouse.

Dylan Moutachi, Janek Hyzewicz, Pauline Roy, Mégane Lemaitre, Damien Bachasson, Helge Amthor, Olli Ritvos, Zhenlin Li, Denis Furling, Onnik Agbulut, Arnaud Ferry.

  Limited knowledge exists regarding the chronic effect of muscular exercise on muscle function in a murine model of severe Duchenne muscular dystrophy (DMD). Here we determined the effects of 1 month of voluntary wheel running (WR), 1 month of enforced treadmill running (TR) and 1 month of mechanical overloading resulting from the removal of the synergic muscles (OVL) in mice lacking both dystrophin and desmin (DKO). Additionally, we examined the effect of activin receptor administration (AR). DKO mice, displaying severe muscle weakness, atrophy and greater susceptibility to contraction-induced functional loss, were exercised or treated with AR at 1 month of age and in situ force production of lower leg muscle was measured at the age of 2 months. We found that TR and OVL increased absolute maximal force and the rate of force development of the plantaris muscle in DKO mice. In contrast, those of the tibialis anterior (TA) muscle remained unaffected by TR and WR. Furthermore, the effects of TR and OVL on plantaris muscle function in DKO mice closely resembled those in mdx mice, a less severe murine DMD model. AR also improved absolute maximal force and the rate of force development of the TA muscle in DKO mice. In conclusion, exercise training improved plantaris muscle weakness in severely affected dystrophic mice. Consequently, these preclinical results may contribute to fostering further investigations aimed at assessing the potential benefits of exercise for DMD patients, particularly resistance training involving a low number of intense muscle contractions. KEY POINTS: Very little is known about the effects of exercise training in a murine model of severe Duchenne muscular dystrophy (DMD). One reason is that it is feared that chronic muscular exercise, particularly that involving intense muscle contractions, could exacerbate the disease. In DKO mice lacking both dystrophin and desmin, characterized by severe lower leg muscle weakness, atrophy and fragility in comparison to the less severe DMD mdx model, we found that enforced treadmill running improved absolute maximal force of the plantaris muscle, while that of tibialis anterior muscle remained unaffected by both enforced treadmill and voluntary wheel running. Furthermore, mechanical overloading, a non-physiological model of chronic resistance exercise, reversed plantaris muscle weakness. Consequently, our findings may have the potential to alleviate concerns and pave the way for exploring the prescription of endurance and resistance training as a viable therapeutic approach for the treatment of dystrophic patients. Additionally, such interventions may serve in mitigating the pathophysiological mechanisms induced by physical inactivity.

Keywords:  Duchenne muscular dystrophy; chronic muscular exercise; endurance training; maximal force; mice; resistance training

DOI:  https://doi.org/10.1113/JP286425
J Diabetes Complications. 2024 Jun 13. pii: S1056-8727(24)00124-7. [Epub ahead of print]38(8): 108798

Muscle mitochondrial function is impaired in adults with type 1 diabetes.

Daniel Gottlieb, Layla A Abushamat, Kristen J Nadeau, Judith G Regensteiner, Jane E B Reusch, Kalie L Tommerdahl, John Rice, Leslie A Knaub, Cynthia M F Monaco, Thomas J Hawke, Christopher G R Perry, Melanie G Cree, Irene E Schauer.

   AIMS: Type 1 diabetes has been associated with mitochondrial dysfunction. However, the mechanism of this dysfunction in adults remains unclear.
METHODS: A secondary analysis was conducted using data from several clinical trials measuring in-vivo and ex-vivo mitochondrial function in adults with type 1 diabetes (n = 34, age 38.8 ± 14.6 years) and similarly aged controls (n = 59, age 44.6 ± 13.9 years). In-vivo mitochondrial function was assessed before, during, and after isometric exercise with 31phosphorous magnetic resonance spectroscopy. High resolution respirometry of vastus lateralis muscle tissue was used to assess ex-vivo measures.
RESULTS: In-vivo data showed higher rates of anaerobic glycolysis (p = 0.013), and a lower maximal mitochondrial oxidative capacity (p = 0.012) and mitochondrial efficiency (p = 0.024) in adults with type 1 diabetes. After adjustment for age and percent body fat maximal mitochondrial capacity (p = 0.014) continued to be lower and anaerobic glycolysis higher (p = 0.040) in adults with type 1 diabetes. Ex-vivo data did not demonstrate significant differences between the two groups.
CONCLUSIONS: The in-vivo analysis demonstrates that adults with type 1 diabetes have mitochondrial dysfunction. This builds on previous research showing in-vivo mitochondrial dysfunction in youths with type 1 diabetes and suggests that defects in substrate or oxygen delivery may play a role in in-vivo dysfunction.

Keywords:  (31)phosphorous magnetic resonance spectroscopy; High-resolution respirometry; Insulin resistance; Mitochondrial function; Muscle

DOI:  https://doi.org/10.1016/j.jdiacomp.2024.108798
Mol Med. 2024 Jul 12. 30(1): 101

RNA editing regulates glutamatergic synapses in the frontal cortex of a molecular subtype of Amyotrophic Lateral Sclerosis.

Korina Karagianni, Dimitra Dafou, Konstantinos Xanthopoulos, Theodoros Sklaviadis, Eirini Kanata.

   BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a highly heterogenous neurodegenerative disorder that primarily affects upper and lower motor neurons, affecting additional cell types and brain regions. Underlying molecular mechanisms are still elusive, in part due to disease heterogeneity. Molecular disease subtyping through integrative analyses including RNA editing profiling is a novel approach for identification of molecular networks involved in pathogenesis.
METHODS: We aimed to highlight the role of RNA editing in ALS, focusing on the frontal cortex and the prevalent molecular disease subtype (ALS-Ox), previously determined by transcriptomic profile stratification. We established global RNA editing (editome) and gene expression (transcriptome) profiles in control and ALS-Ox cases, utilizing publicly available RNA-seq data (GSE153960) and an in-house analysis pipeline. Functional annotation and pathway analyses identified molecular processes affected by RNA editing alterations. Pearson correlation analyses assessed RNA editing effects on expression. Similar analyses on additional ALS-Ox and control samples (GSE124439) were performed for verification. Targeted re-sequencing and qRT-PCR analysis targeting CACNA1C, were performed using frontal cortex tissue from ALS and control samples (n = 3 samples/group).
RESULTS: We identified reduced global RNA editing in the frontal cortex of ALS-Ox cases. Differentially edited transcripts are enriched in synapses, particularly in the glutamatergic synapse pathway. Bioinformatic analyses on additional ALS-Ox and control RNA-seq data verified these findings. We identified increased recoding at the Q621R site in the GRIK2 transcript and determined positive correlations between RNA editing and gene expression alterations in ionotropic receptor subunits GRIA2, GRIA3 and the CACNA1C transcript, which encodes the pore forming subunit of a post-synaptic L-type calcium channel. Experimental data verified RNA editing alterations and editing-expression correlation in CACNA1C, highlighting CACNA1C as a target for further study.
CONCLUSIONS: We provide evidence on the involvement of RNA editing in the frontal cortex of an ALS molecular subtype, highlighting a modulatory role mediated though recoding and gene expression regulation on glutamatergic synapse related transcripts. We report RNA editing effects in disease-related transcripts and validated editing alterations in CACNA1C. Our study provides targets for further functional studies that could shed light in underlying disease mechanisms enabling novel therapeutic approaches.

Keywords:  ALS-Ox; Amyotrophic Lateral Sclerosis; Frontal cortex; Glutamatergic synapse; Molecular subtype; RNA editing

DOI:  https://doi.org/10.1186/s10020-024-00863-2
Am J Physiol Cell Physiol. 2024 Jul 09.

Lactate promotes fatty acid oxidation by the TCA cycle and mitochondrial respiration in muscles of obese mice.

Soi-Yi Park, Su-Ryun Jung, Jong-Yeon Kim, Yong-Woon Kim, Hoon-Ki Sung, So-Young Park, Kyung-Oh Doh, Jin-Ho Koh.

  Lower oxidative capacity in skeletal muscles (SKMs) is a prevailing cause of metabolic diseases. Exercise not only enhances the fatty acid oxidation (FAO) capacity of SKMs but also increases lactate levels. Given that lactate may contribute to tricarboxylic acid cycle (TCA) flux and impact monocarboxylate transporter 1 in the SKMs, we hypothesize that lactate can influence glucose and fatty acid (FA) metabolism. To test this hypothesis, we investigated the mechanism underlying lactate-driven FAO regulation in the SKM of mice with diet-induced obesity (DIO). Lactate was administered to DIO mice immediately after exercise over three weeks. We found that increased lactate levels enhanced energy expenditure mediated by fat metabolism during exercise recovery and decreased triglyceride levels in DIO mice SKMs. To determine the lactate-specific effects without exercise, we administered lactate to mice on a high-fat diet (HFD) for eight weeks. Similar to our exercise conditions, lactate increased FAO, TCA cycle activity, and mitochondrial respiration in the SKMs of HFD-fed mice. Additionally, under sufficient FA conditions, lactate increased uncoupling protein-3 abundance via the NADH/NAD+ shuttle. Conversely ATP synthase abundance decreased in the SKMs of HFD mice. Taken together, our results suggest that lactate amplifies the adaptive increase in FAO capacity mediated by the TCA cycle and mitochondrial respiration in SKMs under sufficient FA abundance.

Keywords:  Exercise; Fatty acid oxidation; Lactate; Mitochondrial respiration; TCA cycle

DOI:  https://doi.org/10.1152/ajpcell.00060.2024
Biol Lett. 2024 Jul;20(7): 20240147

Mitochondrion-to-nucleus communication mediated by RNA export: a survey of potential mechanisms and players across eukaryotes.

Giorgio Muneretto, Federico Plazzi, Marco Passamonti.

  The nucleus interacts with the other organelles to perform essential functions of the eukaryotic cell. Mitochondria have their own genome and communicate back to the nucleus in what is known as mitochondrial retrograde response. Information is transferred to the nucleus in many ways, leading to wide-ranging changes in nuclear gene expression and culminating with changes in metabolic, regulatory or stress-related pathways. RNAs are emerging molecules involved in this signalling. RNAs encode precise information and are involved in highly target-specific signalling, through a wide range of processes known as RNA interference. RNA-mediated mitochondrial retrograde response requires these molecules to exit the mitochondrion, a process that is still mostly unknown. We suggest that the proteins/complexes translocases of the inner membrane, polynucleotide phosphorylase, mitochondrial permeability transition pore, and the subunits of oxidative phosphorylation complexes may be responsible for RNA export.

Keywords:  mito-nuclear interactions; mitochondrial export; mitochondrial retrograde response; regulatory RNAs; small mitochondrial highly transcribed RNAs

DOI:  https://doi.org/10.1098/rsbl.2024.0147
Neurotherapeutics. 2024 Jul 06. pii: S1878-7479(24)00074-6. [Epub ahead of print] e00388

Reversal of cognitive deficits in FUSR521G amyotrophic lateral sclerosis mice by arimoclomol and a class I histone deacetylase inhibitor independent of heat shock protein induction.

Mari Carmen Pelaez, Frédéric Fiore, Nancy Larochelle, Afrooz Dabbaghizadeh, Mario Fernández Comaduran, Danielle Arbour, Sandra Minotti, Laetitia Marcadet, Martine Semaan, Richard Robitaille, Josephine N Nalbantoglu, Chantelle F Sephton, Heather D Durham.

  Protein misfolding and mislocalization are common to both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Maintaining proteostasis through induction of heat shock proteins (HSP) to increase chaperoning capacity is a rational therapeutic strategy in the treatment of ALS. However, the threshold for upregulating stress-inducible HSPs remains high in neurons, presenting a therapeutic obstacle. This study used mouse models expressing the ALS variants FUSR521G or SOD1G93A to follow up on previous work in cultured motor neurons showing varied effects of the HSP co-inducer, arimoclomol, and class I histone deacetylase (HDAC) inhibitors on HSP expression depending on the ALS variant being expressed. As in cultured neurons, neither expression of the transgene nor drug treatments induced expression of HSPs in cortex, spinal cord or muscle of FUSR521G mice, indicating suppression of the heat shock response. Nonetheless, arimoclomol, and RGFP963, restored performance on cognitive tests and improved cortical dendritic spine densities. In SOD1G93A mice, multiple HSPs were upregulated in hindlimb skeletal muscle, but not in lumbar spinal cord with the exception of HSPB1 associated with astrocytosis. Drug treatments improved contractile force but reduced the increase in HSPs in muscle rather than facilitating their expression. The data point to mechanisms other than amplification of the heat shock response underlying recovery of cognitive function in ALS-FUS mice by arimoclomol and class I HDAC inhibition and suggest potential benefits in counteracting cognitive impairment in ALS, frontotemporal dementia and related disorders.

Keywords:  Amyotrophic lateral sclerosis; Arimoclomol; FUS; Frontotemporal dementia; Heat shock proteins; Histone deacetylase inhibitor

DOI:  https://doi.org/10.1016/j.neurot.2024.e00388